A COMBINED COMPUTATIONAL AND EXPERIMENTAL STUDY ON THE LIGAND-GATING IN CNG AND

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们赞赏雷周和Steven A.Siegelbaum对MRAC MCB060027的更新申请，这是一项关于CNG和HCN通道中配体门控的计算和实验相结合的研究。我们发现，两位匿名评审者的大部分评论都非常有建设性，有助于我们进一步改进最初的提案。正如分配工作人员在提案评论中所引用的那样，审查员1的主要技术关切之一是技术转让的应用存在弱点。实际上，我们几乎完全按照评审者1的描述进行了TI(首先去除静电，然后是VDW相互作用；比较了从蛋白质中去除配体与从本体溶剂中去除配体之间的差异)。然而，我们担心文件的大小(已经15页)，所以我们没有在续签申请中提供所有的技术细节或初步结果。在这里，我们仔细地回答了两位审查员提出的关切，并添加了这些技术细节以及相关的初步数据。我们希望这项回应连同原来的续期申请，将可消除这些疑虑，并使这项建议可被接纳，以便我们可以继续进行这项最新机场发展策略续期申请所建议的研究。谢谢你的考虑。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We appreciate the comments on the renewal application for MRAC MCB060027, A combined computational and experimental study on the ligand - gating in CNG and HCN channels, by Lei Zhou and Steven A. Siegelbaum. We found that most of the comments from both anonymous reviewers were very constructive and helpful for us to further improve the original proposal. As quoted in the Proposal Comments by Allocation Staff, one of the major technical concerns by reviewer 1 is on the weakness in the application of TI. Actually we had carried out the TI almost exactly as described by reviewer 1 (first removing electrostatic and then VDW interactions; comparing the difference between removing ligand from protein and versus removing it from bulk solvent). However, we were concerned with the file size (already 15 pages) so that we didnt present all the technical details or preliminary results in the renewal application. Here we carefully address concerns raised by both reviewers and add those technical details together with the related preliminary data. We hope that this response together with the original renewal application will satisfy these concerns and enable this proposal to be found acceptable so that we may continue the research proposed in this MRAC renewal application. Thank you for your consideration.